Devices and methods for treatment of heart failure and associated conditions

ABSTRACT

Devices and methods of use identification, treatment, and/or management of heart failure and/or associated conditions. Methods may include providing a baroreflex therapy system, providing an implantable measurement device proximate a blood vessel of a patient, the implantable measurement device including a plurality of electrodes, determining an impedance of the blood vessel with the implantable measurement device over a time period of at least one cardiac cycle, generating at least one signal representative of a pressure waveform based on the impedance, activating, deactivating or otherwise modulating the baroreflex therapy system to deliver a therapy to treat heart failure based at least in part on the at least one signal representative of the pressure waveform.

RELATED APPLICATIONS

The present application claims priority to U.S. Provisional PatentApplication No. 61/061,938, entitled “Devices and Methods for Treatmentof Heart Failure and Associated Conditions,” filed Jun. 16, 2008, thedisclosure of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates generally to medical devices and methodsof use for the treatment and/or management of heart failure andassociated conditions, and more specifically to devices and methods forcontrolling the baroreflex system for the treatment, diagnosis and/ormanagement of heart failure and associated conditions and theirunderlying causes.

BACKGROUND OF THE INVENTION

Hypertension, or high blood pressure, is a major cardiovascular disorderthat is estimated to affect over 50 million people in the United Satesalone, and is a leading cause of heart failure and stroke. It is theprimary cause of death in over 42,000 patients per year and is listed asa primary or contributing cause of death in over 200,000 patients peryear in the United States alone. Hypertension occurs in part when thebody's smaller blood vessels (arterioles) constrict, causing an increasein blood pressure. Because the blood vessels constrict, the heart mustwork harder to maintain blood flow at the higher pressures. Sustainedhypertension may eventually result in damage to multiple body organs,including the kidneys, brain, eyes and other tissues, causing a varietyof maladies associated therewith. The elevated blood pressure may alsodamage the lining of the blood vessels, accelerating the process ofatherosclerosis and increasing the likelihood that a blood clot maydevelop. This could lead to a heart attack and/or stroke.

Sustained high blood pressure may eventually result in an enlarged anddamaged heart (hypertrophy), which may lead to heart failure. Heartfailure is the final common expression of a variety of cardiovasculardisorders, including ischemic heart disease. It is characterized by aninability of the heart to pump enough blood to meet the body's needs andresults in fatigue, reduced exercise capacity and poor survival. It isestimated that approximately 5,000,000 people in the United Statessuffer from heart failure, directly leading to 39,000 deaths per yearand contributing to another 225,000 deaths per year.

Heart failure results in the activation of a number of body systems tocompensate for the heart's inability to pump sufficient blood. Many ofthese responses are mediated by an increase in the level of activationof the sympathetic nervous system, as well as by activation of multipleother neurohormonal responses. Generally speaking, this sympatheticnervous system activation signals the heart to increase heart rate andforce of contraction to increase the cardiac output; it signals thekidneys to expand the blood volume by retaining sodium and water; and itsignals the arterioles to constrict to elevate the blood pressure. Thecardiac, renal and vascular responses increase the workload of theheart, further accelerating myocardial damage and exacerbating the heartfailure state.

Heart failure can be generally classified into two categories: systolicand diastolic heart failure. The heart contracts and relaxes with eachheartbeat—these phases are referred to as systole (the contractionphase) and diastole (the relaxation phase). Systolic heart failure (SHF)is characterized by low ejection fraction. In patients with diastolicheart failure (DHF), contraction may be normal but relaxation of theheart may be impaired. This impairment is generally caused by astiffening of the ventricles. Such impairment is referred to asdiastolic dysfunction and if severe enough to cause pulmonary congestion(increased pressure and fluid in the blood vessels of the lungs),diastolic heart failure. DHF patients differ from those patients withSHF, in that DHF patients may have a “normal” ejection fraction.However, because the ventricle doesn't relax normally, the pressurewithin the ventricle increases and the blood filling the ventricleexceeds what is “normal”. People with certain types of cardiomyopathymay also have diastolic dysfunction.

Left ventricular hypertrophy refers to a thickening of the leftventricle as a result of increased left ventricular load. Leftventricular hypertrophy can be a significant marker for cardiovasculardisorders and most common complications include arrhythmias, heartfailure, ischemic heart disease, and sudden death. Although leftventricular hypertrophy (LVH) increases naturally with age, it is morecommon in people who have high blood pressure or have other heartproblems. Because LVH usually develops in response to hypertension,current treatment and prevention mainly includes managing hypertension.Typical diagnosis involves the use of echocardiograms (ECHO) andelectrocardiograms (ECG).

The SphygmoCor system (AtCor) provides a non-invasive assessment of thecardiovascular system and autonomic function. The SphygmoCor waveformprovides physicians with clinically important information using avariety of cardiovascular parameters including augmentation index,augmentation pressure, central pulse pressure, central systolicpressure, and ejection duration. The SphygmoCor system comprises anon-invasive pressure transducer that uses a radial artery (externalwrist) measurement and BP monitor. It works by using the pressure probeto record the pressure wave at the radial artery, which is thencalibrated with the brachial blood pressure. However, this system doesnot provide a direct measurement of pressure, and the system is not ableto be used as an implanted, continuous system.

Vascular stiffness in aging and its relation to cardiovascular diseaseis an important topic of current research. Vascular stiffness has beenproposed as a risk factor for overall cardiovascular morbidity andmortality because of its suggested role in elevated blood pressure,increased left ventricular mass and heart failure. Current therapiestargeting vascular stiffness, therefore, include those prescribed forthese conditions, such as hypertension drug therapy. Pulse pressure is aknown, simple measurement that can be used as a surrogate to aorticstiffness. Additionally, wave reflections can be inferred from detailedcomputer-aided pulse wave contour analysis, such as with the AtCorSphygmoCor system.

Heart failure is known to be a multi-organ disease and there is recentevidence that the gut (including the splanchnic circulation) plays animportant role in cardiac diseases. The circulatory system of humansincludes the pulmonary circulation and the systemic circulation. Thepulmonary circulation ensures deoxygenated blood is returned to thelungs and oxygenated blood returned to the heart, while the systemiccirculation ensures that oxygenated blood is supplied to the body. Thesystemic circulation includes the splanchnic circulation (or visceralcirculation), which ensures that digestive organs receive blood throughthe vessels supplying the abdominal viscera. Acute decompensated heartfailure or pulmonary congestion develops as a result of blood beingredistributed from the splanchnic circulation to the pulmonarycirculation, manifesting in fluid build-up in the chest and an inabilityof the patient to breathe. The specific mechanism of this transfer offluids between the two is not yet fully understood.

The current standard of care for a patient exhibiting congestion is avariety of drugs, including diuretics, which causes excretion of fluidthrough the renal system. Splanchnic nerve stimulation has beendescribed in the art to treat shock. For example, WO 2006/0031902 toMachado et. al teaches a method of treating hemodynamic derangement andcontrolling the mobilization of splanchnic circulation by stimulatingthe splanchnic nerve. Neither drug therapy, nor nerve stimulationtherapy has been successful in providing a controlled therapy forcongestive heart failure or acute decompensated heart failure.

A number of drug treatments have been proposed for the management ofhypertension, heart failure, and other cardiovascular disorders. Theseinclude vasodilators to reduce the blood pressure and ease the workloadof the heart, diuretics to reduce fluid overload, inhibitors andblocking agents of the body's neurohormonal responses, and othermedicaments. Such medications can be effective for a short time, butcannot be used for expended periods because of side effects. Varioussurgical procedures have also been proposed for these maladies. Forexample, heart transplantation has been proposed for patients who sufferfrom severe, refractory heart failure. Alternatively, an implantablemedical device such as a ventricular assist device (VAD) may beimplanted in the chest to increase the pumping action of the heart.Alternatively, an intra-aortic balloon pump (IABP) may be used formaintaining heart function for short periods of time, but typically nolonger than one month.

Each of these approaches may be at least partly beneficial to patients,however each of the therapies has its own disadvantages. For example,drug therapy is often incompletely effective. Drugs often have unwantedside effects and may need to be given in complex regimens. These andother factors contribute to poor patient compliance with medicaltherapy. Drug therapy may also be expensive, adding to the health carecosts associated with these disorders. Likewise, surgical approaches arevery costly, may be associated with significant patient morbidity andmortality and may not alter the natural history of the disease.

Accordingly, there continues to be a need for improved devices andmethods for diagnosing, treating and/or managing high blood pressure,heart failure, and their associated cardiovascular and nervous systemdisorders.

SUMMARY OF THE INVENTION

Embodiments of the present invention comprises devices and methods ofuse for the diagnosis, treatment and/or management of heart failure andassociated conditions. In one embodiment, the present inventioncomprises devices and methods for controlling the baroreflex system of apatient for the treatment and/or management of heart failure andassociated conditions and their underlying causes.

In one embodiment, the present invention comprises methods and devicesof sensing, measuring, and monitoring parameters indicative ofcardiovascular function. In one embodiment, an impedance sensor isprovided on, in or proximate a blood vessel to obtain waveform data ofblood movement in the vessel. The obtained waveform data providesinformation relating to a forward wave and a reflected wave of a heartbeat and also to the augmentation index. In another embodiment, theobtained waveform may be used to calculate parameters indicative ofcardiovascular disorders and associated conditions, such as splanchniccirculation or left ventricular mass. In a further embodiment, thesensed waveform may be used to provide feedback in conjunction with adelivered therapy, such as a baroreflex therapy or a cardiacresynchronization therapy.

Embodiments of the present invention recognize that real-time centralpressure of a patient could provide diagnostic and clinically relevantinformation and that it would be advantageous to provide a means forobtaining direct, real-time central pressure waveform data and use suchinformation for display in a clinical setting. It would additionally beadvantageous to use such information in a closed-loop system to optimizetherapies.

Embodiments of the present invention also recognize the advantages ofbeing able to sense and monitor the movement of fluids between thesplanchnic and pulmonary circulations and be able to use thisinformation to titrate drug and other therapies. Embodiments of thepresent invention may also provide controlled therapy to modulate thefluid distribution in a patient, to treat congestion or prevent ensuingcongestion.

Embodiments of the present invention also recognize the advantage ofbeing able to measure and monitor vascular stiffness. Certainembodiments of the present invention provide a means for closed-loopmonitoring of vascular stiffness in order to use such information toprovide and optimize therapies to prevent and reduce vascular stiffness.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention may be more completely understood in consideration of thefollowing detailed description of various embodiments of the inventionin connection with the accompanying drawings, in which:

FIG. 1A is a graph of the cardiac phases.

FIG. 1B is a graph of a PV loop.

FIG. 2 is a graph depicting a reflected cardiac pressure wave before andafter application of a baroreflex therapy to a canine according to anembodiment of the present invention.

FIG. 3 is a graph depicting a reflected cardiac pressure wave before andafter application of a baroreflex therapy to a human according to anembodiment of the present invention.

FIG. 4 is an example of a central pressure waveform.

FIG. 5 is a central pressure waveform obtained by an embodiment of thepresent invention.

FIG. 6 is a table of parameters that may be derived from the waveform ofFIG. 5.

FIG. 6A illustrates additional information that can be derived from thecentral pressure waveform.

FIG. 7 is a chart depicting a reduction in augmentation index followingapplication of a baroreflex therapy according to an embodiment of thepresent invention.

FIG. 8A is a table depicting patient physiological parameters followingapplication of a baroreflex therapy according to an embodiment of thepresent invention.

FIG. 8B is a table depicting patient physiological parameters followingapplication of a baroreflex therapy according to an embodiment of thepresent invention.

FIG. 8C is a table depicting patient physiological parameters followingapplication of a baroreflex therapy according to an embodiment of thepresent invention.

FIG. 9A is a graph depicting a PV loop before and after application of abaroreflex therapy according to an embodiment of the present invention.

FIG. 9B is a table depicting patient physiological parameters followingapplication of a baroreflex therapy according to an embodiment of thepresent invention.

FIG. 10A is a graph depicting a PV loop before and after application ofa baroreflex therapy according to an embodiment of the presentinvention.

FIG. 10B is a table depicting patient physiological parameters followingapplication of a baroreflex therapy according to an embodiment of thepresent invention.

FIG. 11 is a chart depicting patient physiological parameters followingapplication of a baroreflex therapy according to an embodiment of thepresent invention.

FIG. 12 is a chart depicting levels of markers indicative of heartfailure before and after application of a baroreflex therapy accordingto an embodiment of the present invention.

FIG. 13 is a group of charts depicting physiological parameters ofcontrol subjects compared to subjects that have received baroreflextherapy according to an embodiment of the present invention.

While the invention is amenable to various modifications and alternativeforms, specifics thereof have been shown by way of example in thedrawings and will be described in detail. It should be understood,however, that the intention is not to limit the invention to theparticular embodiments described. On the contrary, the intention is tocover all modifications, equivalents, and alternatives falling withinthe spirit and scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description should be read with reference to thedrawings in which similar elements in different drawings are numberedthe same. The drawings, which are not necessarily to scale, depictillustrative embodiments and are not intended to limit the scope of theinvention.

Methods for treating heart failure and associated conditions in asubject typically comprise identifying a patient in need of treatmentand stimulating a baroreflex with a baroreflex activation device toimprove the symptoms and conditions associated with heart failure. Insome variations, the baroreflex activation device is implanted proximatethe baroreceptor, and in other variations, the baroreflex activationdevice is external. The stimulation provided by the baroreflexactivation device may be any suitable stimulation. For example, it maybe electrical stimulation, mechanical stimulation, thermal stimulation,chemical stimulation, or combinations thereof. In some variations thestimulation is electrical stimulation. The stimulation may be pulsed orcontinuous.

For additional information pertaining to cardiovascular anatomy andexemplary baroreceptor and baroreflex therapy systems, reference is madeto the following patents and patent applications: Published U.S. PatentApplication No. 2005/0154418 to Kieval et al., Published U.S. PatentApplication No. 2005/0251212 to Kieval et al., Published U.S. PatentApplication No. 2006/0293712 to Kieval et al., Published U.S. PatentApplication No. 2006/0004417 to Rossing et al., Published U.S. PatentApplication No. 2006/0074453 to Kieval et al., Published U.S. PatentApplication No. 2009/0143837 to Rossing et al., U.S. Pat. No. 6,522,926to Kieval et al., and U.S. Pat. No. 6,985,774 to Kieval et al., thedisclosures of which are hereby incorporated by reference in theirentireties.

In one embodiment, the invention provides a system and methods forobtaining a blood pressure waveform, and using the pressure waveform toderive parameters indicative of cardiovascular disorders. The waveformmay be obtained independent of a therapy, such as for a stand-alonediagnostic and monitoring system, or the waveform may be used to providefeedback to a closed-loop therapy system. In such closed-loop system,one can use the waveform data to program, or adjust therapy to improvesaid cardiovascular disorders, and continuously monitor the status ofthe therapy in order to provide targeted, precise and controlledtherapy.

The pressure waveform may be obtained with the use of electrodespositioned on, in or proximate a blood vessel, such as the carotid sinusor carotid artery. The electrodes measure impedance along or through theblood vessel. Methods and devices for obtaining blood vessel impedancemeasurements can be found in patent application Ser. No. 12/345,558,filed Dec. 28, 2008, entitled “Measurement of Patient PhysiologicalParameters,” the disclosure of which is incorporated by reference in itsentirety. From the obtained impedance values, a waveform can begenerated, such as in FIG. 5. The waveform may comprise a forward wavecomponent and a reflected wave component. Suitable electrodearrangements for obtaining the waveform include an extravascular wraphaving a plurality of electrodes positioned radially or longitudinallyon the vessel, or an intravascular device resembling anelectrophysiology catheter, having at least a plurality of electrodes.Signals from the sensor can be measured continuously or on anappropriate basis to gather hemodynamic information for the patient.

In one embodiment, the waveform data is used to determine theaugmentation index, which is indicative of arterial stiffness. Thesystem and methods of this embodiment increase venous reserve andcapacitance, thereby improving vascular elasticity and vascularcompliance with the majority of bodily vessels.

In one embodiment, the waveform data is indicative of LV mass and/or LVmass index. Referring to the waveform of FIG. 6A, the shaded arearepresents extra energy expenditure (Ew) imposed on the left ventricleduring ejection. Referring still to FIG. 6A, Ew can be calculated as2.09*(Ps—Pl)*(Ed−Tr), wherein Tr is the reflected wave time. This energyexpenditure correlates with LV mass index, such that LV mass index canbe monitored and logged with a waveform generated from an implantedtransarterial impedance measurement device.

Well-known historical data on primary wave and augmentation index from avariety of sources demonstrated that reflected waves arrive earlier andcentral augmentation increases markedly with advancing age. Such dataalso supports speculation that central aortic stiffness and forward waveamplitude are the primary mechanism for increased central and peripheralsystolic and pulse pressure with advancing age in healthy adults. Itwould be advantageous to reduce the amplitude of forward and reflectedwaves, as well as delay the reflected wave.

To demonstrate the efficacy of the device and methods of the invention,experiments were performed on canines. FIG. 2 depicts the reduction inamplitude of the reflected wave as well as the delay in time of thereflected wave. This data suggests a significant improvement in thevascular properties after delivery of a baroreflex activation therapy(BAT).

To demonstrate the efficacy of the present invention on human patients,studies were performed that measured the reflected wave before and afterdelivery of baroreflex activation therapy. FIG. 3 depicts the resultsillustrating the efficacy of baroreflex activation therapy in bothreducing the amplitude of the reflected wave and delaying the time ofthe wave.

It is possible to derive many parameters from a pressure waveform. FIG.4 depicts a “textbook” pressure waveform, while FIG. 5 depicts apressure waveform obtained by a transarterial impedance measurementaccording to embodiments of the present invention. Many parametersobtainable from the pressure waveform are presented in FIG. 6. While thederivation of these parameters from a pressure waveform has previouslybeen known, until now it has not been possible to obtain such a waveformfrom a chronically-implanted arrangement, allowing real-time monitoringof a patient.

In one embodiment, the processed signal is displayable on a computermonitor so as to be readable by a physician. The physician may selectone or more of the indices of interest. Such indices may include those,for example, in FIG. 6. In one embodiment, pulse wave velocity isderived. In one embodiment, the invention provides algorithms andcomputer-readable media to automatically generate the parameters ofinterest. In one embodiment, the invention may provide automatedfeedback to the therapy device in order to adjust or modify therapybased on these waveform-derived indices.

In one embodiment, the system derives augmentation index (AI)information and relies on the AI to adjust therapy. For example, if anAI is above a predetermined threshold level, baroreflex activationtherapy is applied until the desired result (reduced AI) is achieved. Inorder to prove efficacy of baroreflex activation therapy in reducing AIin humans, an experiment was performed that delivered baroreflexactivation therapy acutely to human implant patients. FIG. 7 depicts theresults which conclude that AI was reduced when baroreflex activationtherapy was delivered acutely in a human patient. Because AI is anindicator of arterial stiffness/compliance, this illustrates thatbaroreflex activation therapy affects arterial compliance, therebyreducing stiffness of vessels.

Benefits

Examination and analysis of pressure waveform data provides new insightto the effects of a baroreflex activation therapy. Embodiments of theinvention have beneficial applications for diagnosing and managing heartfailure and associated conditions. It has been observed experimentallythat baroreflex activation therapy works by affecting a number ofstructures and function in the patient. Without limiting the scope ofthe invention, below is a list of observed benefits of the currentinvention and how each benefit may be measured or confirmed with thesystem of the invention.

One benefit is improved splanchnic circulation by way of increasingreservoir capacity of splanchnic circulation, resulting in net fluidtransfer from lungs to gut. This fluid transfer may be measured by forexample, trans thoracic impedance sensors that monitor fluid; otherfluid sensors located for example in a vessel of the gut and a vessel ofthe pulmonary circulation; a sensor to measure elevated pulmonary arterypressure; monitoring weight gain; or monitoring incline during sleep.

Other benefits include reduced end diastolic pressure (EDP); increasedcardiac output, measured by stroke volume and heart rate and by pulsecontour methodology of the central pressure waveform; reduced diastolicstiffness, measured by −dp/dt, tau, edpvr; improved cardiac elasticity,measured by for example augmentation index; improved cardiaccontractility, measured by arterial PV loop information derived from thecentral pressure waveform; +dp/dt, end systolic pressure-volumerelationship (espvr); reduced likelihood that lone atrial fibrillationwill occur; reduced likelihood that ventricular arrhythmias will occur;beneficial ventricular remodeling over time as evidenced by the changesin central pressure waveform; reduced detrimental remodeling that haspreviously occurred in the heart; reduced exercise intolerance asmeasured by patient activity with activity sensors; improved gutpermeability; improved lung permeability; alleviation of fluid retentionas measured by weight and other fluid sensors. Example embodiments ofthe present invention are described below.

Heart Failure

In one embodiment, sensors are used to monitor the fluids in a patient.Such sensors can be selected form a group consisting of edema sensorsand other fluid/wetness sensors, chemical sensors, such as sensors toassay circulating plasma catecholamine, norepinephrine, angiotensin orBNP sensors, pressure sensors such as transarterial impedance, transthoracic impedance, pulmonary artery or other intravascular pressuresensors and other pressure sensors. Such sensors can be located in avariety of locations including the heart, vessels, internal and externalin order to measure parameters indicative of heart failure. Such sensorsand methods of using them can be used as a stand alone system to monitorthe build-up of fluids in the pulmonary circulation that is indicativeof, for example heart failure. In another embodiment, such sensors canbe used in a closed loop system with a therapy. In this embodiment,sensors monitor the presence or increase of fluids in the pulmonarycirculation and provide baroreflex activation therapy. The sensorssubsequently monitor the fluids in the splanchnic circulation andmodulate therapy in order to move the fluids from pulmonary circulationto splanchnic circulation. Once the sensors sense the movement of fluids(that the pulmonary fluid has been reduced to an appropriate level), thetherapy can be halted or adjusted to maintain the result. One couldadditionally use non-invasive methods to measure parameters conceived ofby the inventions such as MRI and echocardiography.

In one embodiment, sensors are used to monitor the left ventricular massof the patient in order to assess and monitor left ventricularhypertrophy. The methods of the invention could be used to treatpatients exhibiting hypertrophy or as a monitor for ensuing hypertrophyin order to prevent it. Recent studies indicate that LVH was common at 1year after heart transplantation, present in 83% of heart transplantrecipients. Heart transplant recipients with severe LVH hadsignificantly decreased survival. Therefore, the methods of theinvention can be useful in the heart transplant population to monitorthe development of hypertrophy and prevent it, thus improving outcomesfor these patients. The sensors of the invention and methods of usingthem can be used as a stand alone system to monitor the LV mass,indicative of, for example left ventricular hypertrophy and heartfailure or ensuing heart failure. In another embodiment, such sensorscan be used in a closed loop system with a therapy. In this embodiment,sensors monitor the LV mass index in a patient and provide baroreflexactivation therapy. The sensors subsequently monitor the LV mass andmodulate therapy in order to reduce the LV mass. Once the sensors sensethe reduction in LV mass, the therapy can be halted or adjusted tomaintain the result.

To demonstrate efficacy of baroreflex activation therapy in humanpatients, experiments were performed to measure LV mass and relatedparameters. The experimental study results in FIGS. 8A and 8B using theLV Mass Index measurements and therapy methods of the invention showthat baroreflex activation therapy reduced the following: bloodpressure, LV wall thickness, LV mass, LV mass index (LVMI), and relativewall thickness.

Recent studies suggest that therapies which increase the diameter of theproximal aorta and left ventricular outflow tract (LVOT) may lower pulsepressure (PP) and thus may beneficially impact cardiovascular risk. Asillustrated in FIG. 8B, baroreflex activation therapy increases LVOTdiameter while reducing blood pressure, pulse pressure, and LVMI.Benefits are in addition to those achieved with intensive drug therapy.

In one embodiment, the present invention may reduce myocardial oxygenconsumption (MVO2). MVO2 refers to the amount of oxygen consumed (orrequired) by the heart muscle for a contraction, and is increased underconditions such as in a heart failure patient, when heart rate isincreased, contractility is increased, ventricular volume is increased,ventricular pressure is increased, etc. As described herein, heartfailure is a cyclic mechanism where the body tries to compensate inresponse to reduced cardiac output. The increase in sympathetic toneresults in increase in heart rate (to maintain cardiac output), anincrease in peripheral arterial resistance (to maintain blood pressure),etc., and also an increase in MVO2 (to meet the myocardial oxygendemand). Thus, an increase in MVO2 means the heart is working muchharder to meet the demand. Therefore, MVO2 is important in theassessment of heart failure, and therapy that reduces MVO2 would beuseful in treating heart failure.

Baroreflex therapy works to reverse the sympathetic response and resultsin reduced MVO2 in patients as seen in FIG. 8C. Measuring the MVO2indicates how hard the heart is working to contract and also whether thebaroreflex therapy can be deactivated or reduced or whether it shouldcontinue or be increased until MVO2 falls within an accepted range(generally 7,000-10,000 bpm*mmHg in patients with systolic bloodpressure of 120 mmHg and heart rate of 65-80 bpm). As can be seen inFIG. 8C, baroreflex therapy reduced MVO2 to acceptable levels within 4months and continued to reduce it through 13 months.

In another embodiment, the present invention may improve arterialelasticity and/or vascular compliance. Arterial compliance is determinedby structural factors, such as collagen and elastin, and functionalfactors, such as vasoactive neurohormones. The elastic behavior ofconduit arteries contributes importantly to left ventricular functionand aortic flow. Increased pulse pressure, an index of the pulsatilehemodynamic load, is a risk factor for the development of congestiveheart failure. The increased pulsatile load that results from a decreasein arterial compliance reduces left ventricular stroke volume more sowhen the contractile state is depressed than in the normally functioningventricle. Therefore, impaired arterial elasticity is particularlydeleterious in patients with congestive heart failure.

Baroreflex therapy works to improve such factors as venous reserve andcapacitance, thus improving elasticity of vessels. Measuring arterialcompliance by means of such measures as augmentation index, and alsopulse pressure (which is an indicator of aortic stiffness) can indicatea patient's propensity for or current heart failure status. FIG. 8Cdepicts measurements of arterial compliance with echocardiogram and ismeasured in units of mL/mmHg. The normal range for patients using thismeasurement is approximately 1-2 mL/mmHg depending on age (as compliancegenerally is reduced with age). As seen in FIG. 8C, baroreflex therapyresults in increased arterial compliance at 4 months and continues to 13months. Pulse pressure is also reduced.

Arterial PV Loops for Real-time Measurement of Heart and ArterialFunction

In one embodiment, the invention provides an implantable, real-timepressure-volume loop monitoring device. Pressure-volume loops and theirrelationships to various mechanisms of the heart have been describedsince the early 1900s. For example, Starling described the relationshipbetween filling pressure of the ventricle and stroke volume in 1914. Thewell known Frank-Starling mechanism describes the ability of the heartto match an increased venous return with an augmented stroke volume. PVloops are currently used for measuring pressure and volumeperioperatively.

Generally, left ventricular (LV) PV loops are derived from pressure andvolume information found in a cardiac cycle diagram. To generate a PVloop for the left ventricle, the left ventricular pressure (LVP) isplotted against LV volume at multiple time points during a completecardiac cycle. Various parameters related to cardiac function can bederived from LV loops. For example, parameters related to informationsuch as ventricular filling, contraction, ejection, relaxation, enddiastolic volume and end diastolic pressure can be obtained from PVloops and are known in the art. FIGS. 1A and 1B illustrate the cardiacphases and a typical PV loop.

In this embodiment, the left ventricular end-systolic pressure andstroke volume are measured and assessed continuously or as needed by aphysician. In one embodiment, the system and methods of the inventionprovide a device that stimulates a baroreflex in order to reduce leftventricular pressure and increase left ventricular volume. In oneembodiment, the device receives information from the PV loop monitor andadjusts therapy to optimize the result. In one embodiment, the pressureportion of the PV loop is derived from a transarterial pressurewaveform. In one embodiment, the pressure portion is derived from an LVconductance catheter. In one embodiment, the pressure portion is derivedfrom a pressure sensor in the aorta and the signal is obtained duringthe systole phase of the cardiac cycle. In one embodiment, the volumeportion is derived from transarterial impedance waveform, which isderived from a flow measurement. In another embodiment, a separatesensor capable of determining blood flow is provided, and is used togenerate the volume portion of the PV loop. In one embodiment reducedleft ventricular pressure is confirmed by the implanted, real time,continuous PV loop of the invention. In one embodiment, the increasedleft ventricular volume is confirmed by the implanted, real time,continuous PV loop of the invention.

At least a portion of the PV loop can be generated from an impedancemeasurement on the aorta. During systole, the aortic valve is open, suchthat the pressure in the aorta the same as the pressure in the leftventricle. The impedance of the aorta is measured, and a pressurewaveform is generated from the measured impedance values. In oneembodiment, the pressure waveform may be processed to obtain a valueindicative of flow, which can be integrated over time to obtain volume.From these values, the “top” portion of an LV loop (corresponding tosystole) can be generated.

To demonstrate efficacy of baroreflex activation therapy effects onhemodynamic measures, experiments were performed on canines. FIGS.9A-10B depict the reduction in LV pressure and increase in LV volumeafter BAT; FIG. 10B illustrates the hemodynamic characteristics.Referring specifically to FIG. 9A, the PV loop illustrates lowerarterial pressures and increased stroke volumes following BAT. FIG. 9Billustrates that in a normal canine subject, application of baroreflexactivation therapy reduces heart rate, reduces cardiac load (pressures),and slightly reduces the speed with which the heart contracts (dpdt).Reduced fatigue and improved coronary perfusion should occur in apatient that has received baroreflex activation therapy.

Referring to FIGS. 10A-10B, a reduction in heart rate and an increase ineach of stroke volume, ejection fraction, and cardiac output can be seenfollowing application of baroreflex activation therapy. Further, areduction in Tau (time constant of LV relaxation) and an increase inpeak filling rate indicate improved diastolic function. Therate-pressure-product (RPP) decrease indicates the heart is consumingless energy, despite the increased cardiac output.

Combined Baroreflex Therapy and Vagal Nerve Stimulation

In one embodiment, the invention comprises a system that improves thenormalization of sympathetic/parasympathetic balance by combiningbaroreflex activation therapy with a vagal nerve electrode that providesefferent vagal nerve stimulation to the heart for more precise androbust heart rate control, or provides a stimulus to inhibit efferentvagal nerve activity to the heart if heart rate drops too low withbaroreflex activation therapy. The advantages of this therapy for heartfailure are that vagal nerve stimulation alone lowers heart rate butdoes not affect the vasculature. Current baroreflex activation therapyaffects both heart rate and the vasculature but does not provideselective control of heart rate and blood pressure and may be perceivedto cause precipitous drops in arterial pressure in certain heart failurepatients. By providing an additional mechanism to augment the heart ratedrop, this invention allows for greater heart rate and pressure controlthan either system alone.

The parasympathetic nervous system has a complementary relationship withthe sympathetic nervous system. The body uses these two systems toregulate blood pressure. Stimulation or enhancement of theparasympathetic nervous system generally causes a decrease in bloodpressure. Stimulating or enhancing the sympathetic nervous system, onthe other hand, generally causes blood pressure to increase. If cardiacoutput is insufficient to meet demand (i.e., the heart is unable to pumpsufficient blood), the brain activates a number of body systems,including the heart, kidneys, blood vessels, and other organs/tissues tocorrect this.

In one embodiment, baroreflex activation therapy is achieved byelectrodes placed around the carotid sinus, and vagal nerve stimulationis achieved by an electrode placed around the right vagus nerve. Inother embodiments, vagal nerve stimulation is achieved by an electrodeplaced intravascularly, for example either in the jugular vein forstimulating the right vagus nerve, or in the superior vena cava tostimulate the cardiac branches of the vagus nerve. Using sensors formonitoring heart rate and blood pressure, the combined system altersbaroreflex activation therapy intensity and vagal nerve stimulationintensity to achieve target heart rate reductions without compromisingblood pressure. For example, if the heart rate target has not beenachieved with baroreflex activation therapy, but the blood pressuretarget value has been achieved, vagal nerve stimulation is applied toreduce heart rate further.

The system is also programmable to alter intensities of baroreflexactivation therapy and vagal nerve stimulation to achieve target bloodpressures and heart rates in a more efficient manner than baroreflexactivation therapy or vagal nerve stimulation alone. For example, whenhigh intensity baroreflex activation therapy is required to achievetarget heart rate but blood pressure is not too low, the system operatesin a closed-loop fashion to reduce intensity of baroreflex activationtherapy as much as possible, without losing any of the pressureresponse, while increasing vagal nerve stimulation to account for anyloss of heart rate response. The system uses an algorithm to monitorblood pressure, heart rate, baroreflex activation therapy intensity, andvagal nerve stimulation intensity, to find the most efficientcombination of baroreflex activation therapy and vagal nerve stimulationintensities to achieve target blood pressure and heart rate values. Inthe event that the baroreflex activation therapy intensity required forachieving a target pressure response causes heart rate to drop too far,the system inhibits efferent vagal nerve activity by providing vagalnerve stimulation to inhibit nerve traffic in the efferent direction,thereby counteracting the parasympathetic activity enhancement bybaroreflex activation therapy.

Baroreceptor signals in the arterial vasculature are used to activate anumber of body systems which collectively may be referred to as thebaroreflex system. For the purposes of the present invention, it will beassumed that the “receptors” in the venous and cardiopulmonaryvasculature (including the pulmonary artery) and heart chambers functionanalogously to the baroreceptors in the arterial vasculature, but suchassumption is not intended to limit the present invention in any way. Inparticular, the methods described herein will function and achieve atleast some of the stated therapeutic objectives regardless of theprecise and actual mechanism responsible for the result. Moreover, thepresent invention may activate baroreceptors, mechanoreceptors,pressoreceptors, stretch receptors, chemoreceptors, or any other venous,heart, or cardiopulmonary receptors which affect the blood pressure,nervous system activity, and neurohormonal activity in a manneranalogous to baroreceptors in the arterial vasculation. For convenience,all such venous receptors will be referred to collectively herein as“baroreceptors” or “receptors” unless otherwise expressly noted.

While there may be small structural or anatomical differences amongvarious receptors in the vasculature, for the purposes of someembodiments of the present invention, activation may be directed at anyof these receptors and/or nerves and/or nerve endings from thesereceptors so long as they provide the desired effects. In particular,such receptors will provide afferent signals, i.e., signals to thebrain, which provide the blood pressure and/or volume information to thebrain. This allows the brain to cause “reflex” changes in the autonomicnervous system, which in turn modulate organ activity to maintaindesired hemodynamics and organ perfusion. Stimulation of the baroreflexsystem may be accomplished by stimulating such receptors, nerves, nervefibers, or nerve endings, or any combination thereof.

Arrhythmias

A study was performed examining the effects of baroreflex activationtherapy on the induction of ventricular tachycardia or ventricularfibrillation in canines with intracoronary microembolization-inducedadvanced heart failure (LV ejection fraction ˜20%). Canines with heartfailure underwent programmed ventricular stimulation performed from theright ventricular apex. Stimulation parameters of the baroreflex therapysystem were chosen for each subject in order to achieve a desired levelof baroreflex activation therapy, measured as an approximate 10-20% dropin arterial pressure under anesthesia (1% isofluorane). Devices werethen programmed to these stimulation parameters at the beginning of thetherapy period and remained at these settings throughout the three monththerapy period.

The results in FIG. 11 show that in addition to improving LV functionand attenuating LV remodeling, long-term baroreflex activation therapyreduces the incidence of inducible lethal ventricular arrhythmias incanine patients with chronic advanced heart failure. This added benefitof baroreflex activation therapy provides further support for the use ofthis novel approach for the treatment of chronic heart failure.

CRT Therapy

In one embodiment, the pressure waveform is generated with informationfrom a sensor located in for example an artery and used to input to acardiac resynchronization therapy (CRT) device. In this embodiment, theCRT pulse is adjusted based on the measured time and/or amplitudevariables obtained from the waveform. In one embodiment, the CRTprogramming adjustment can be made manually by for example a physician.In one embodiment, the pressure sensor is connected to the CRT therapydevice and programming can be done automatically by the CRT device. Inone embodiment, the device determines if the CRT therapy is working andadjusts the baroreflex activation therapy accordingly. For example, thedevice may use information for the derived pressure waveform anddetermine if the CRT is improving for example the reflected wave. If itis not, baroreflex activation therapy is applied until a desiredreflected wave modification is seen.

Norepinephrine and Angiotensin II:

In one embodiment, a closed-loop system monitors circulating markersindicative of heart failure or ensuing heart failure. Possible markerscould include but are not limited to norepinephrine, angiotensin II,aldosterone or BNP. Other known markers in the art could be used. In oneembodiment, the HF marker monitoring system is used in combination withthe baroreflex activation therapy system to monitor and adjust therapyin order to optimize efficacy and efficiency of the device.

To prove efficacy of baroreflex activation therapy to reduce markersindicative of heart failure, studies were performed to measurenorepinephrine (NE) and angiotensin II (ANG) plasma levels before andafter baroreflex activation therapy in dogs with HF. Results indicatethat baroreflex activation therapy of the carotid sinus delays theincrease in plasma NE and ANG II and significantly enhances survival indogs with pacing-induced HF. Chronic baroreflex activation therapyreduces renal vasoconstriction during exercise in dogs withpacing-induced HF. These data suggest that baroreflex activation therapymay be of benefit in the treatment of severe heart failure. FIGS. 12 and13 depict the results of three separate experiments. FIG. 12 depictsmRNA expression of Angiotensin AT-2 Receptors (du) in dogs. FIG. 13depicts the results of whole body NE kinetics during baroreflexactivation therapy, including mean arterial pressure, plasma NE levels,NE spillover and NE clearance.

Various modifications to the embodiments of the inventions may beapparent to one of skill in the art upon reading this disclosure. Forexample, persons of ordinary skill in the relevant art will recognizethat the various features described for the different embodiments of theinventions can be suitably combined, un-combined, and re-combined withother features, alone, or in different combinations, within the spiritof the invention. Likewise, the various features described above shouldall be regarded as example embodiments, rather than limitations to thescope or spirit of the inventions. Therefore, the above is notcontemplated to limit the scope of the present inventions.

Persons of ordinary skill in the relevant arts will recognize that theinventions may comprise fewer features than illustrated in anyindividual embodiment described above. The embodiments described hereinare not meant to be an exhaustive presentation of the ways in which thevarious features of the inventions may be combined. Accordingly, theembodiments are not mutually exclusive combinations of features; rather,the inventions may comprise a combination of different individualfeatures selected from different individual embodiments, as understoodby persons of ordinary skill in the art.

Any incorporation by reference of documents above is limited such thatno subject matter is incorporated that is contrary to the explicitdisclosure herein. Any incorporation by reference of documents above isfurther limited such that no claims included in the documents areincorporated by reference herein. Any incorporation by reference ofdocuments above is yet further limited such that any definitionsprovided in the documents are not incorporated by reference hereinunless expressly included herein.

For purposes of interpreting the claims for the embodiments of thepresent inventions, it is expressly intended that the provisions ofSection 112, sixth paragraph of 35 U.S.C. are not to be invoked unlessthe specific terms “means for” or “step for” are recited in a claim.

1. A method of treating heart failure, comprising: providing abaroreflex therapy system; providing an implantable measurement deviceproximate a blood vessel of a patient, the implantable measurementdevice including a plurality of electrodes; and providing a controlsystem coupled to the baroreflex therapy system and the implantablemeasurement device, the control system programmed to automatically:determine an impedance of the blood vessel with the implantablemeasurement device over a time period of at least one cardiac cycle;generate at least one signal representative of a pressure waveform basedon the impedance; activate, deactivate or otherwise modulate thebaroreflex therapy system to deliver a therapy to treat heart failurebased at least in part on the at least one signal representative of thepressure waveform.
 2. The method of claim 1, wherein the control systemis further programmed to automatically: determine an augmentation indexfrom the at least one signal representative of a pressure waveform;activate, deactivate or otherwise modulate the baroreflex therapy systembased on the augmentation index.
 3. The method of claim 1, wherein thecontrol system is further programmed to automatically: determinearterial compliance from the at least one signal representative of apressure waveform; activate, deactivate or otherwise modulate thebaroreflex therapy system based on the arterial compliance.
 4. Themethod of claim 1, wherein the control system is further programmed toautomatically: determine a myocardial oxygen consumption from the atleast one signal representative of a pressure waveform; activate,deactivate or otherwise modulate the baroreflex therapy system based onthe myocardial oxygen consumption.
 5. The method of claim 1, wherein thecontrol system is further programmed to automatically: determine anaugmentation index from the at least one signal representative of apressure waveform; activate, deactivate or otherwise modulate thebaroreflex therapy system based on the augmentation index.
 6. The methodof claim 1, wherein the control system is further programmed toautomatically: determine a parameter indicative of left ventricle massfrom the at least one signal representative of a pressure waveform;activate, deactivate or otherwise modulate the baroreflex therapy systembased on the parameter indicative of left ventricle mass.
 7. A method,comprising: providing a baroreflex therapy system; providing animplantable measurement device proximate a blood vessel of a patient,the implantable measurement device including a plurality of electrodes;providing a control system coupled to the baroreflex therapy system andthe implantable measurement device; and providing instructions recordedon a tangible medium for operating the control system to deliver atherapy to treat heart failure, the instructions comprising: determiningan impedance of the blood vessel with the implantable measurement deviceover a time period of at least one cardiac cycle; generating at leastone signal representative of a pressure waveform based on the impedance;activating, deactivating or otherwise modulating the baroreflex therapysystem to deliver a therapy to treat heart failure based at least inpart on the at least one signal representative of the pressure waveform.8. A method, comprising: implanting a plurality of electrodes proximatean aorta of a patient; automatically determining an impedance of theaorta with the electrodes over a time period of at least one cardiaccycle; automatically generating at least one signal representative of apressure waveform based on the impedance; automatically generating apressure-volume loop based at least in part on the at least one signalrepresentative of the pressure waveform.
 9. The method of claim 8,further comprising: providing a baroreflex therapy system; delivering atherapy with the baroreflex therapy system based at least in part on thepressure-volume loop.
 10. The method of claim 9, further comprising:activating, deactivating or otherwise modulating the baroreflex therapysystem based at least in part on the at least one signal representativeof the pressure waveform.
 11. The method of claim 8, further comprising:implanting a sensor proximate the aorta configured to measure bloodflow; generating a pressure-volume loop based at least in part oninformation received from the sensor.
 12. A method, comprising:providing a plurality of electrodes; providing a baroreflex therapysystem; and providing instructions recorded on a tangible medium, theinstructions comprising: implanting the plurality of electrodesproximate an aorta of a patient; determining an impedance of the aortawith the electrodes over a time period of at least one cardiac cycle;generating at least one signal representative of a pressure waveformbased on the impedance; generating a pressure-volume loop based at leastin part on the at least one signal representative of the pressurewaveform; and delivering a therapy with the baroreflex therapy systembased at least in part on the pressure-volume loop.
 13. A method,comprising: implanting one or more sensors in a patient; implanting abaroreflex therapy system; automatically detecting with the one or moresensors an undesirable level of fluid in a pulmonary circulation of thepatient; and automatically delivering therapy with the baroreflextherapy system in response to the detecting an undesirable level offluid in the pulmonary circulation to reduce the level of fluid in thepulmonary circulation.
 14. The method of claim 13, further comprising:upon detecting with the one or more sensors an acceptable level of fluidin the pulmonary circulation, automatically delivering a second therapywith the baroreflex therapy system to maintain the acceptable level offluid in the pulmonary circulation.
 15. The method of claim 13, whereinautomatically delivering the second therapy comprises cessation oftherapy.
 16. A method, comprising: providing a baroreflex activationdevice; providing one or more sensors; and providing instructionsrecorded on a tangible medium, the instructions comprising: implantingthe baroreflex activation device within a patient; implanting the one ormore sensors within the patient; detecting with the one or more sensorsan undesirable level of fluid in a pulmonary circulation of the patient;and delivering therapy with the baroreflex therapy system in response tothe detecting an undesirable level of fluid in the pulmonary circulationto reduce the level of fluid in the pulmonary circulation.
 17. A system,comprising: an implantable baroreflex activation device; an implantablemeasurement device configured to be implanted proximate a blood vesselof a patient, the implantable measurement device including a pluralityof electrodes; and a control system coupled to the baroreflex activationdevice and the implantable measurement device, the control systemprogrammed to automatically: determine an impedance of the blood vesselwith the implantable measurement device over a time period of at leastone cardiac cycle; generate at least one signal representative of apressure waveform based on the impedance; activate, deactivate orotherwise modulate the baroreflex therapy system to deliver a therapy totreat heart failure based at least in part on the at least one signalrepresentative of the pressure waveform.
 18. The system of claim 17,wherein the implantable measurement device is integrated with theimplantable baroreflex activation device.